Human autoimmune diseases, of which more than 70 are known, afflict 5-10% of the US population. Some, such as rheumatoid arthritis, multiple sclerosis and diabetes occur at high frequency while others, such as pemphigus vulgaris have a low frequency. All of these diseases are linked to specific histocompatibilty proteins. The purpose of this application is to use mouse model of multiple sclerosis to investigate improvements in a drug which is currently in wide use for the therapy of this disease and to study in detail the mechanisms through which these drugs work. In particular we intend: 1. To investigate the use of a novel random amino acid copolymer poly(FYAK)n [a second generation Copaxone[unreadable]1/2] for the amelioration of experimental autoimmune encephalomyelitis (EAE) in mice (as a model for their potential use in the amelioration of multiple sclerosis, MS) by: a) fully characterizing copolymer- specific, antigen-non-specific regulatory T cell lines generated in response to the random amino acid copolymer poly(F, Y, A, K)n. These regulatory T cells appear to be different from those already described and their generation is a major mechanism through which the copolymers function, b) investigating the amelioration of EAE by poly(F, Y, A, KJ^n in new models, c) synthesizing and examining the properties of additional amino acid copolymers, for example poly(V, W, A, K)n and poly(V, Y, A, K)n, to optimize efficacy in EAE. 2. To investigate the use of a peptide 15mer of defined sequence (a third generation Copaxone[unreadable]1/2) for the amelioration of EAE by: a) extending the studies of amelioration of EAE by the J5 peptide 15mer, including careful comparison with poly(F, Y, A, K)n and Copaxone in three different protocols termed vaccination, prevention and treatment;b) characterizing fully regulatory T cell lines and clones generated after immunization with the J5 peptide 15mer, similarly to the above studies with amino acid copolymers;c) investigating further modifications of the J5 peptide 15mer;d) synthesizing MHC class II tetramers binding the J5 peptide 15mer with which to measure the frequency of JS-specific regulatory T cells tissues and in peripheral blood. This method could provide a means of establishing the frequency with which the J5 peptide 15mer needs to be administered to achieve maximum therapeutic efficacy;e) generating regulatory T cells in vivo by targeting the J5 peptide 15merto immature dendritic cells in vivo;f) Tracking regulatory T cells in vivo using a polymorphic marker and multiphoton intravital microscopy. __